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1.
Nat Commun ; 12(1): 1064, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594056

RESUMO

Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment.


Assuntos
Síndrome do Ovário Policístico/patologia , Adiposidade , Animais , Animais Recém-Nascidos , Peso Corporal , Análise Discriminante , Modelos Animais de Doenças , Dislipidemias/patologia , Sistema Endócrino/patologia , Ciclo Estral , Feminino , Teste de Tolerância a Glucose , Gonadotropinas/farmacologia , Hormônios/sangue , Humanos , Secreção de Insulina , Análise dos Mínimos Quadrados , Lipídeos/química , Masculino , Troca Materno-Fetal , Análise Multivariada , Ovário/patologia , Ovário/fisiopatologia , Fenótipo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Ratos Wistar , Reprodução , Maturidade Sexual
2.
Life Sci ; 269: 119038, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33453239

RESUMO

OBJECTIVE: Glucose-dependent insulinotropic polypeptide receptor (GIPR) has been identified as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). Therefore, we developed the anti-GIPR antagonistic monoclonal antibody (mAb) alone and in combination with DPP-4 inhibitor as potential therapeutic strategy for treating obesity and dyslipidemia based on this genetic evidence. METHODS: Fully neutralized GIPR activity of GIPR-monoclonal antibody (mAb) was assessed by regulating the in vitro production of cAMP in the mouse GIPR stably expressing cells. Chronic efficacies of GIPR-mAb alone and in combination with DPP-4 inhibitor Sitagliptin in diabetic or DIO mice were both investigated. Multiple metabolic parameters including body weight, glucose level, fat mass, lipid metabolism-related indicators as well as H&E staining and immunohistochemical analysis were performed. Role of GIPR in pancreatic cells on regulating fat metabolism was explored in GIPR ß-cell knockout mouse model. RESULTS: Chronic treatment of GIPR-mAb improved body weight control, glucose metabolism, and was associated with reduced fat mass, enhanced pancreatic function and exchange ratio of the resting respiratory in diabetic mice. In addition, further study of anti-GIPR mAb combined with Sitagliptin in DIO mice demonstrated significantly improved weight loss compare to the both monomer treatment. Furthermore, we demonstrated important role of GIPR in ß-cell in regulating the fat mass and response to antagonistic GIPR-mAb in a conditional GIPR-knockout mouse. CONCLUSION: Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor provide preclinical therapeutic approaches to treat obesity.


Assuntos
Anticorpos Monoclonais/farmacologia , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Dislipidemias/tratamento farmacológico , Nefropatias/tratamento farmacológico , Obesidade/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Animais , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Quimioterapia Combinada , Dislipidemias/etiologia , Dislipidemias/patologia , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Obesidade/etiologia , Obesidade/patologia , Receptores dos Hormônios Gastrointestinais/imunologia , Receptores dos Hormônios Gastrointestinais/fisiologia , Perda de Peso
3.
Nat Commun ; 12(1): 213, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431899

RESUMO

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.


Assuntos
Dieta Hiperlipídica , Exossomos/metabolismo , Resistência à Insulina/genética , Fosfatidilcolinas/metabolismo , Regulação para Cima/genética , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/complicações , Dislipidemias/genética , Dislipidemias/patologia , Células Epiteliais/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Fezes , Regulação da Expressão Gênica , Intolerância à Glucose , Proteínas de Fluorescência Verde/metabolismo , Humanos , Insulina/metabolismo , Interleucina-6/sangue , Intestinos/citologia , Lipídeos/química , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Tetraspanina 30/metabolismo , Fator de Necrose Tumoral alfa/sangue
4.
Artigo em Inglês | MEDLINE | ID: mdl-32961276

RESUMO

We studied the mechanism of HDL denaturation with concomitant apoA-I dissociation with HDL preparations from 48 patients with a wide range of plasma HDL-C and evaluated the contribution of lipid-free apoA-I into cholesterol efflux from macrophage, in particular, mediated by cholesterol transporter ABCA1. We prepared HDL by precipitation of apoB-containing lipoproteins by polyethylene glycol and used the chaotropic agent urea to denature HDL preparations. Apo-I dissociation from urea-treated HDL was assessed by the increase of preß-band fraction with agarose gel electrophoresis followed by electro transfer and immunodetection and by the increase of ABCA1-mediated efflux of fluorescent analogue BODIPY-Cholesterol from RAW 264.7 macrophages. The HDL denaturation is governed by a single transition to fully dissociated apoA-I and the transition cooperativity decreases with increasing HDL-C. The apoA-I release depends on phospholipid concentration of HDL preparation and HDL compositional and structural heterogeneity and is well described by apolipoprotein partition between aqueous and lipid phases. Dissociated apoA-I determines the increase of ABCA1-mediated efflux of BODIPY-Cholesterol from RAW 264.7 macrophages to patient HDL. The increase in apoA-I dissociation is associated with the increase of ABCA1 gene transcript in peripheral blood mononuclear cells from patients. The low level of plasma HDL particles may be compensated by their increased potency for apoA-I release, thus suggesting apoA-I dissociation as a new HDL functional property.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I/metabolismo , HDL-Colesterol/sangue , Dislipidemias/sangue , Ureia/química , Transportador 1 de Cassete de Ligação de ATP/genética , Adulto , Animais , Apolipoproteína A-I/genética , Transporte Biológico , Índice de Massa Corporal , Compostos de Boro/química , LDL-Colesterol/sangue , Estudos de Coortes , Dislipidemias/genética , Dislipidemias/patologia , Corantes Fluorescentes/química , Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polietilenoglicóis/química , Desnaturação Proteica/efeitos dos fármacos , Células RAW 264.7 , Coloração e Rotulagem/métodos , Triglicerídeos/sangue , Ureia/farmacologia
6.
Life Sci ; 266: 118870, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310040

RESUMO

AIM: Betel-nut, a popular masticatory among Southeast Asian populations is a class I carcinogen, previously associated with dyslipidemia and aberrant lipid metabolism, and is reported to be used more frequently by females, than males. This study investigates the potential of repurposing the anti-diabetic drug, vildagliptin, a dipeptidyl peptidase-4 inhibitor, for alleviating the oncogenic condition in female Swiss Albino mice administered an aqueous extract of betel-nut (AEBN) orally (2 mg ml-1) for 24 weeks. MAIN METHODS: Tissues were investigated by histopathological, immunohistochemical and apoptosis assays. Biochemical analyses of oxidative stress markers and lipid profile were performed using different tissues and sera. The expressions of different proteins involved in lipid metabolism and oncogenic pathways were evaluated by Western blotting. KEY FINDINGS: AEBN induced carcinogenesis primarily in the liver by significantly impairing AMPK signaling, inducing oxidative stress, activating Akt/mTOR signaling, increasing Ki-67 immunoreactivity and cyclin D1 expression, and significantly diminishing apoptosis. Co-administration of AEBN with vildagliptin (10 mg kg-1 body weight) for 8 weeks reduced liver dysplasia, and significantly decreased free palmitic acid, increased free oleic acid, normalized lipid profile, decreased oxidative stress, cyclin D1 expression, Ki-67 immunoreactivity, and Bcl2 expression, and increased the ratio of apoptotic/non-apoptotic cells. Mechanistically, vildagliptin elicited these physiological and molecular alterations by restoring normal AMPK signaling and reducing the cellular expressions of FASN and HMGCR, restoring AMPK-dependent phosphorylation of p53 at Ser-15 and reducing Akt/mTOR signaling. SIGNIFICANCE: These results indicate that vildagliptin may alleviate betel-nut induced carcinogenesis in the liver of female mice.


Assuntos
Areca/toxicidade , Inibidores da Dipeptidil Peptidase IV/farmacologia , Neoplasias Hepáticas Experimentais/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/toxicidade , Vildagliptina/farmacologia , Animais , Carcinogênese , Dislipidemias/induzido quimicamente , Dislipidemias/patologia , Dislipidemias/prevenção & controle , Feminino , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Transdução de Sinais
7.
Sci Rep ; 10(1): 17458, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060704

RESUMO

We aim to study the association of hyperlipidemia and statin use with COVID-19 severity. We analysed a retrospective cohort of 717 patients admitted to a tertiary centre in Singapore for COVID-19 infection. Clinical outcomes of interest were oxygen saturation ≤ 94% requiring supplemental oxygen, intensive-care unit (ICU) admission, invasive mechanical-ventilation and death. Patients on long term dyslipidaemia medications (statins, fibrates or ezetimibe) were considered to have dyslipidaemia. Logistic regression models were used to study the association between dyslipidaemia and clinical outcomes adjusted for age, gender and ethnicity. Statin treatment effect was determined, in a nested case-control design, through logistic treatment models with 1:3 propensity matching for age, gender and ethnicity. All statistical tests were two-sided, and statistical significance was taken as p < 0.05. One hundred fifty-six (21.8%) patients had dyslipidaemia and 97% of these were on statins. Logistic treatment models showed a lower chance of ICU admission for statin users when compared to non-statin users (ATET: Coeff (risk difference): - 0.12 (- 0.23, - 0.01); p = 0.028). There were no other significant differences in other outcomes. Statin use was independently associated with lower ICU admission. This supports current practice to continue prescription of statins in COVID-19 patients.


Assuntos
Infecções por Coronavirus/patologia , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pneumonia Viral/patologia , Idoso , Betacoronavirus/isolamento & purificação , Estudos de Casos e Controles , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Dislipidemias/complicações , Dislipidemias/patologia , Feminino , Humanos , Imunidade Inata , Unidades de Terapia Intensiva , Contagem de Leucócitos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Estudos Retrospectivos , Índice de Gravidade de Doença
8.
PLoS One ; 15(9): e0238163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881885

RESUMO

OBJECTIVE: We evaluated the effects of grape juice (Vitis labrusca L.) on dyslipidemia, resistance to insulin, and left ventricular hypertrophy (LVH) in mice homozygous for the absence of the LDL receptor gene (LDLr -/-) under a hyperlipidemic diet. METHODOLOGY: We divided 30 male mice (3 months old) into three groups (n = 10); the HL group was fed a high-fat diet, the HLU group received a high-fat diet and 2 g/kg/day of grape juice, and the HLS group was fed a high-fat diet and simvastatin (20 mg/kg/day). We assessed the blood pressure profile of the mice. We also determined the levels of C-reactive protein (CRP) and lipid profile, glycemic and insulinemic profiles, and calculated the HOMA-IR. Cardiomyocyte hypertrophy, interstitial collagen deposit, and the expression of CD40 ligand (CD40L) and metalloproteinases 2 and 9 were assessed immunohistologically. RESULTS: After 60 days, the mice treated with grape juice showed similar results as those of the group treated with simvastatin. The use of grape fruit attenuated dyslipidemia and insulin resistance and significantly increased the levels of high cholesterol density lipoproteins (HDLc). The antioxidant potential of phenolic compounds associated with the increase in HDLc levels in the mice of the HLU group prevented the development of LVH and arterial hypertension since it inhibited the inflammatory response induced by the CD40 pathway and its ligand CD40L. Consequently, there was a lower expression of MMP-2 and MMP-9 and lower serum levels of CRP. CONCLUSION: Grape juice has a hypolipidemic and cardiac protective potential, presenting a similar effect as that of simvastatin through a direct antioxidant action of phenolic compounds, or indirectly, via antioxidant action and anti-inflammatory activity of the HDLc. These results suggest that grape juice is a functional food possessing a high potential to prevent cardiovascular diseases.


Assuntos
Dislipidemias/patologia , Sucos de Frutas e Vegetais , Hipertrofia Ventricular Esquerda/prevenção & controle , Vitis/química , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Ligante de CD40/genética , Ligante de CD40/metabolismo , Colágeno/metabolismo , Dieta Hiperlipídica , Dislipidemias/tratamento farmacológico , Sucos de Frutas e Vegetais/análise , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Receptores de LDL/deficiência , Receptores de LDL/genética , Sinvastatina/uso terapêutico , Vitis/metabolismo
9.
Nat Med ; 26(9): 1375-1379, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32778826

RESUMO

The promise of precision medicine lies in data diversity. More than the sheer size of biomedical data, it is the layering of multiple data modalities, offering complementary perspectives, that is thought to enable the identification of patient subgroups with shared pathophysiology. In the present study, we use autism to test this notion. By combining healthcare claims, electronic health records, familial whole-exome sequences and neurodevelopmental gene expression patterns, we identified a subgroup of patients with dyslipidemia-associated autism.


Assuntos
Transtorno Autístico/diagnóstico , Dislipidemias/diagnóstico , Medicina de Precisão/métodos , Transtorno Autístico/genética , Transtorno Autístico/patologia , Dislipidemias/genética , Dislipidemias/patologia , Registros Eletrônicos de Saúde , Exoma/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Lipídeos/sangue , Masculino , Técnicas de Diagnóstico Molecular , Sequenciamento Completo do Exoma
10.
PLoS One ; 15(6): e0234716, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559230

RESUMO

Inspired by the mechanistic correlations between superoxide dismutase 1 (SOD1) and lipid metabolism, the associations of SOD1 single nucleotide polymorphisms (SNPs) with circulating lipid levels were explored. In 2621 Chinese Han adults, randomly recruited from a health examination center without organic diseases, cancers, and pregnancy, three tag SNPs, rs4998557, rs1041740, and rs17880487 selected by Haploview software were genotyped with a probe-based real-time quantitative PCR method. In both genders, most parameters of the dyslipidemia adults were inferior (P < 0.001) to those of the non-dyslipidemia adults, and genotype frequencies of rs4998557 and rs17880487 were significantly different (P < 0.05) between the normal and abnormal subgroups of total cholesterol (TC) or high-density lipoprotein cholesterol (HDLC). Adjusted for confounding factors, logistic regression analyses revealed that in males rs4998557A, rs1041740T, and rs17880487T reduced the risk of high TC and/or LDLC (P < 0.05), and rs4998557A and rs17880487T increased the risk of low HDLC (P < 0.05); but in females, none of the SNPs had associations with any of the lipid parameters (P > 0.05). Conclusively, characterized by a sexual dimorphism, the SOD1 polymorphisms were associated with the lipid disorders in the adult males but not females of the Chinese Han population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Lipídeos/sangue , Caracteres Sexuais , Superóxido Dismutase-1/genética , Adulto , Colesterol/sangue , HDL-Colesterol/sangue , Dislipidemias/genética , Dislipidemias/patologia , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
PLoS One ; 15(5): e0227720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407314

RESUMO

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.


Assuntos
Dislipidemias/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Animais , Comportamento Animal/fisiologia , Relógios Circadianos/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Ácidos Graxos/metabolismo , Gluconeogênese/genética , Glucose/metabolismo , Heterozigoto , Humanos , Metabolismo dos Lipídeos/genética , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Knockout , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miofibrilas/genética , Miofibrilas/metabolismo , Miofibrilas/patologia , Fotoperíodo
12.
Metabolism ; 107: 154226, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277945

RESUMO

BACKGROUND: Aberrant endothelial function is a major contributing factor in cardiovascular disease. Dyslipidemia leads to decreased nitric oxide (NO) bioavailability, an early sign of endothelial failure. Low insulin gene enhancer protein (ISL1) levels decrease healthy NO bioavailability. We hypothesized that the microRNA miR-652-3p negatively regulates endothelial ISL1 expression and that dyslipidemia-induced miR-652-3p upregulation induces aberrant endothelial functioning via ISL1 downregulation. METHODS: Various in vitro experiments were conducted in human umbilical vein endothelial cells (HUVECs). Luciferase assays were performed in HEK293 cells. We constructed a high-fat diet (HFD) Apoe-/- murine model of dyslipidemia and a rat model of low-density lipoprotein (LDL)-induced dyslipidemia to conduct in vivo and ex vivo experiments. RESULTS: Luciferase assays confirmed miR-652-3p's targeting of the ISL1 3'-untranslated region (3'-UTR). Simvastatin blocked oxidized LDL (ox-LDL)-induced increases in miR-652-3p and ox-LDL-induced decreases in ISL1 protein expression, endothelial NO synthase (eNOS) activation, and NO production. Simvastatin's effects were abrogated by miR-652-3p overexpression and phenocopied by miR-652-3p inhibition. The dyslipidemic mouse model exhibited increased miR-652-3p and decreased ISL1 protein levels in the endothelium, effects opposed by simvastatin or miR-652-3p inhibition. The impact of simvastatin in vivo was abolished by overexpressing miR-652-3p or knocking-down ISL1. The rat model of dyslipidemia exhibited a similar pattern of miR-652-3p upregulation, attenuated ISL1 protein levels, decreased eNOS activation, and decreased NO production, effects mitigated by simvastatin. CONCLUSIONS: Dyslipidemia upregulates endothelial miR-652-3p, which decreases ISL1 protein levels, eNOS activation, and NO production. Simvastatin therapy lowers endothelial miR-652-3p expression to protect endothelial function under dyslipidemic conditions.


Assuntos
Dislipidemias/patologia , Dislipidemias/prevenção & controle , Endotélio/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Proteínas com Homeodomínio LIM/biossíntese , MicroRNAs/biossíntese , Fatores de Transcrição/biossíntese , Animais , Apolipoproteínas E/genética , Regulação para Baixo/efeitos dos fármacos , Dislipidemias/genética , Ativação Enzimática , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/efeitos dos fármacos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Cardiovasc Diabetol ; 19(1): 33, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169071

RESUMO

The proprotein convertase subtilisin/kexin type 9 (PCSK9) acts via a canonical pathway to regulate circulating low-density lipoprotein-cholesterol (LDL-C) via degradation of the LDL receptor (LDLR) on the liver cell surface. Published research has shown that PCSK9 is involved in atherosclerosis via a variety of non-classical mechanisms that involve lysosomal, inflammatory, apoptotic, mitochondrial, and immune pathways. In this review paper, we summarized these additional mechanisms and described how anti-PCSK9 therapy exerts effects through these mechanisms. These additional pathways further illustrate the regulatory role of PCSK9 in atherosclerosis and offer an in-depth interpretation of how the PCSK9 inhibitor exerts effects on the treatment of atherosclerosis.


Assuntos
Aterosclerose/enzimologia , LDL-Colesterol/sangue , Diabetes Mellitus/enzimologia , Dislipidemias/enzimologia , Inflamação/enzimologia , Pró-Proteína Convertase 9/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/patologia , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Humanos , Inflamação/sangue , Inflamação/patologia , Macrófagos/enzimologia , Macrófagos/patologia , Placa Aterosclerótica , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico
14.
Acta Diabetol ; 57(7): 861-866, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32114640

RESUMO

AIMS: Hyperreflective foci (HF), detected in the retina of diabetic patients, suggest the presence of microglial activation and migration, while controversies still remain for the origin of HF to be precursors of hard exudates. We investigated the presence of HF and their association with dyslipidemia in serous retinal detachment (SRD)-type diabetic macular edema (DME). METHODS: Forty-two eyes in 42 patients with diabetic retinopathy (DR) and 22 eyes in 22 patients with branch retinal vascular occlusion (BRVO) showing macular edema were included in this study. The medical records and OCT findings were retrospectively reviewed in patients with SRD-type DME and compared with those with BRVO. The mean number of HF, the mean choroidal thickness, and lipid profiles were analyzed and compared between groups. RESULTS: The mean number of HF was significantly higher in DR group compared to BRVO group. Significant correlation of HF was noted with triglycerides (r = 0.523, P = 0.002). Triglycerides were significantly associated with HF by linear regression (ß = 0.012, 95% CI 0.001-0.024, P = 0.034) and remained significantly associated by multiple linear regression (ß = 0.014, 95% CI 0.003-0.025, P = 0.014). CONCLUSIONS: HF on OCT of DME patients could be indicative of activated microglia. HF are associated with dyslipidemia, especially high triglycerides, suggesting inflammatory reaction from dyslipidemia in diabetic retina.


Assuntos
Retinopatia Diabética/complicações , Dislipidemias/complicações , Edema Macular/complicações , Microglia/patologia , Retina/patologia , Descolamento Retiniano/complicações , Adulto , Idoso , Movimento Celular , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/patologia , Dislipidemias/diagnóstico , Dislipidemias/patologia , Feminino , Humanos , Edema Macular/diagnóstico , Edema Macular/patologia , Masculino , Microglia/fisiologia , Pessoa de Meia-Idade , Retina/diagnóstico por imagem , Retina/fisiopatologia , Oclusão da Artéria Retiniana/complicações , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/patologia , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual
15.
Sci Rep ; 10(1): 5102, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198436

RESUMO

Tooth formation can be affected by various factors, such as oral disease, drug administration, and systemic illness, as well as internal conditions including dentin formation. Dyslipidemia is an important lifestyle disease, though the relationship of aberrant lipid metabolism with tooth formation has not been clarified. This study was performed to examine the effects of dyslipidemia on tooth formation and tooth development. Dyslipidemia was induced in mice by giving a high-fat diet (HFD) for 12 weeks. Additionally, LDL receptor-deficient (Ldlr-/-) strain mice were used to analyze the effects of dyslipidemia and lipid metabolism in greater detail. In the HFD-fed mice, incisor elongation was decreased and pulp was significantly narrowed, while histological findings revealed disappearance of predentin. In Ldlr-/- mice fed regular chow, incisor elongation showed a decreasing trend and pulp a narrowing trend, while predentin changes were unclear. Serum lipid levels were increased in the HFD-fed wild-type (WT) mice, while Ldlr-/- mice given the HFD showed the greatest increase. These results show important effects of lipid metabolism, especially via the LDL receptor, on tooth homeostasis maintenance. In addition, they suggest a different mechanism for WT and Ldlr-/- mice, though the LDL receptor pathway may not be the only factor involved.


Assuntos
Dentinogênese/fisiologia , Dislipidemias/patologia , Incisivo/crescimento & desenvolvimento , Metabolismo dos Lipídeos/fisiologia , Receptores de LDL/genética , Animais , Dentina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
16.
Sci Rep ; 10(1): 2848, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071372

RESUMO

A large proportion of cases with chronic conditions including diabetes or pre-diabetes, hypertension and dyslipidemia remain undiagnosed. To include reproductive factors (RF) might be able to improve current screening guidelines by providing extra effectiveness. The objective is to study the relationships between RFs and chronic conditions' biomarkers. A cross-sectional study was conducted. Demographics, RFs and metabolic biomarkers were collected. The relationship of the metabolic biomarkers were shown by correlation analysis. Principal component analysis (PCA) and autoencoder were compared by cross-validation. The better one was adopted to extract a single marker, the general chronic condition (GCC), to represent the body's chronic conditions. Multivariate linear regression was performed to explore the relationship between GCC and RFs. In total, 1,656 postmenopausal females were included. A multi-layer autoencoder outperformed PCA in the dimensionality reduction performance. The extracted variable by autoencoder, GCC, was verified to be representative of three chronic conditions (AUC for patoglycemia, hypertension and dyslipidemia were 0.844, 0.824 and 0.805 respectively). Linear regression showed that earlier age at menarche (OR = 0.9976) and shorter reproductive life span (OR = 0.9895) were associated with higher GCC. Autoencoder performed well in the dimensionality reduction of clinical metabolic biomarkers. Due to high accessibility and effectiveness, RFs have potential to be included in screening tools for general chronic conditions and could enhance current screening guidelines.


Assuntos
Diabetes Mellitus/epidemiologia , Dislipidemias/epidemiologia , Hipertensão/epidemiologia , Estado Pré-Diabético/epidemiologia , Adulto , Idoso , Biomarcadores/sangue , Doença Crônica/epidemiologia , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/patologia , Dislipidemias/diagnóstico , Dislipidemias/patologia , Feminino , Guias como Assunto , Humanos , Hipertensão/diagnóstico , Hipertensão/patologia , Aprendizado de Máquina , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Análise Multivariada , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/patologia , Análise de Componente Principal , Fatores de Risco
17.
Int J Mol Sci ; 21(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019138

RESUMO

Atrial fibrillation (AF) is the most common persistent arrhythmia, and can lead to systemic thromboembolism and heart failure. Aging and metabolic syndrome (MetS) are major risks for AF. One of the most important manifestations of MetS is dyslipidemia, but its correlation with AF is ambiguous in clinical observational studies. Although there is a paradoxical relationship between fasting cholesterol and AF incidence, the beneficial benefit from lipid lowering therapy in reduction of AF is significant. Here, we reviewed the health burden from AF and MetS, the association between two disease entities, and the metabolism of triglyceride, which is elevated in MetS. We also reviewed scientific evidence for the mechanistic links between very low density lipoproteins (VLDL), which primarily carry circulatory triglyceride, to atrial cardiomyopathy and development of AF. The effects of VLDL to atria suggesting pathogenic to atrial cardiomyopathy and AF include excess lipid accumulation, direct cytotoxicity, abbreviated action potentials, disturbed calcium regulation, delayed conduction velocities, modulated gap junctions, and sarcomere protein derangements. The electrical remodeling and structural changes in concert promote development of atrial cardiomyopathy in MetS and ultimately lead to vulnerability to AF. As VLDL plays a major role in lipid metabolism after meals (rather than fasting state), further human studies that focus on the effects/correlation of postprandial lipids to atrial remodeling are required to determine whether VLDL-targeted therapy can reduce MetS-related AF. On the basis of our scientific evidence, we propose a pivotal role of VLDL in MetS-related atrial cardiomyopathy and vulnerability to AF.


Assuntos
Fibrilação Atrial/patologia , Dislipidemias/patologia , Lipoproteínas VLDL/efeitos adversos , Síndrome Metabólica/patologia , Tromboembolia/patologia , Fibrilação Atrial/complicações , Remodelamento Atrial , Dislipidemias/etiologia , Junções Comunicantes/metabolismo , Átrios do Coração/patologia , Humanos , Síndrome Metabólica/etiologia , Tromboembolia/etiologia , Triglicerídeos/metabolismo
18.
Sci Rep ; 10(1): 2565, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054943

RESUMO

There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical "proof of concept" study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet- WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved NASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice.


Assuntos
Citrus/química , Dislipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Dislipidemias/genética , Dislipidemias/patologia , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/patologia , MAP Quinase Quinase 4/genética , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/química , Proteínas Quinases p38 Ativadas por Mitógeno/genética
19.
DNA Cell Biol ; 39(8): 1401-1409, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32077751

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most common female reproductive metabolisms. It is an endocrine disease that affects reproductive women and often exhibits with hyperandrogenemia, insulin resistance (IR), low inflammation, and an increased risk of type 2 diabetes mellitus, metabolic syndrome, and cardiovascular events such as hypertension and dyslipidemia in patients. However, the molecular mechanism of PCOS is still unclear. Recently, an increasing number of studies have shown that the oxidative stress induced by mitochondrial dysfunction has negative effects on IR, lipid metabolism, and follicular development, suggesting that mitochondrial dysfunction plays an essential role in the development of PCOS. Abnormal mitochondrial DNA copy number in patients with PCOS, and mitochondrial gene mutations, has been the focus of research in recent years, and functional mitochondrial diseases have been gradually accepted as a related factor in PCOS. This review is intended to summarize and discuss previous and recent studies and findings on the connections between mitochondrial dysfunction and PCOS.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Mitocôndrias/genética , Síndrome do Ovário Policístico/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/genética , Dislipidemias/patologia , Feminino , Humanos , Hiperandrogenismo/genética , Hiperandrogenismo/patologia , Hipertensão/genética , Hipertensão/patologia , Resistência à Insulina/genética , Mitocôndrias/patologia , Mutação/genética , Síndrome do Ovário Policístico/patologia
20.
PLoS One ; 15(2): e0229336, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32101562

RESUMO

Due to differential treatment responses of patients to pharmacotherapy, drug development and practice in medicine are concerned with personalized medicine, which includes identifying subgroups of population that exhibit differential treatment effect. For time-to-event data, available methods only focus on detecting and testing treatment-by-covariate interactions and may not consider multiplicity. In this work, we introduce the Bayesian credible subgroups approach for time-to-event endpoints. It provides two bounding subgroups for the true benefiting subgroup: one which is likely to be contained by the benefiting subgroup and one which is likely to contain the benefiting subgroup. A personalized treatment effect is estimated by two common measures of survival time: the hazard ratio and restricted mean survival time. We apply the method to identify benefiting subgroups in a case study of prostate carcinoma patients and a simulated large clinical dataset.


Assuntos
Teorema de Bayes , Doenças Cardiovasculares/mortalidade , Interpretação Estatística de Dados , Dislipidemias/mortalidade , Modelos Estatísticos , Neoplasias da Próstata/mortalidade , Idoso , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Simulação por Computador , Dislipidemias/patologia , Dislipidemias/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Medicina de Precisão , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Taxa de Sobrevida , Resultado do Tratamento
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